Department of Women and Children's Health, School of Life Course and Population Health Sciences, Kings College London, London SE1 1UL, UK.
Institute of Reproductive and Developmental Biology, Imperial College London, London W12 0NN, UK.
Endocrinology. 2022 Oct 23;163(12). doi: 10.1210/endocr/bqac161.
Follicle-stimulating hormone (FSH) is a key endocrine regulator of ovarian function. FSH is secreted as 2 macroglycosylation variants: partially glycosylated FSH (FSH21/18) and fully glycosylated FSH (FSH24). FSH21/18 is more potent than FSH24 at binding to and activating the FSH receptor (R). The ratio of FSH21/18:FSH24 has been shown to change with age, with FSH21/18 predominant at reproductive prime, and FSH24 predominant during perimenopause/menopause. How these FSH glycosylation variants modulate ovarian follicle functions remains largely unknown. The aim of this study was to investigate the effect of FSH glycosylation variants of pre-antral follicle function. Pre-antral follicles were isolated from 3- to 5-week-old C57BL/6 mice and treated ±10 ng/mL FSH21/18, FSH24, a ratio of 80:20 FSH21/18:FSH24 (to mimic reproductive prime), 50:50 FSH21/18:FSH24 (perimenopause), or 20:80 FSH21/18:FSH24 (menopause) for up to 96 hours. FSH21/18 and 80:20 FSH21/18:FSH24 increased follicle growth, in comparison with control, contrasting with FSH24 and 20:80 FSH21/18:FSH24. Survival rates were decreased in follicles treated with FSH24 or 20:80 FSH21/18:FSH24, with follicles undergoing basement membrane rupture and oocyte extrusion, increased Caspase3 gene and protein expression, and decreased markers of cell proliferation in FSH24 or 20:80 FSH21/18:FSH24-treated follicles. Moreover, this correlated with differential regulation of key genes modulating follicular functions. Pharmacological inhibitors of key FSH signal pathways suggests FSH21/18 and FSH24 initiate different FSHR signal pathway activation, which may determine their differential effects on follicle growth and survival. These data suggest that the nature of FSH glycosylation modulates the follicular cellular environment to regulate follicle growth and survival and may underpin the increasing ovarian resistance to FSH observed during aging.
卵泡刺激素（FSH）是卵巢功能的关键内分泌调节剂。FSH 作为 2 种糖基化变体分泌：部分糖基化 FSH（FSH21/18）和完全糖基化 FSH（FSH24）。FSH21/18 在与 FSH 受体（R）结合和激活方面比 FSH24 更有效。FSH21/18/FSH24 的比例随年龄而变化，在生殖高峰期以 FSH21/18 为主，在围绝经期/绝经期间以 FSH24 为主。这些 FSH 糖基化变体如何调节卵巢卵泡功能在很大程度上仍然未知。本研究旨在研究前腔卵泡功能的 FSH 糖基化变体的影响。从前 3 至 5 周龄 C57BL/6 小鼠中分离前腔卵泡，并分别用 10ng/mL FSH21/18、FSH24、80:20 FSH21/18:FSH24（模拟生殖高峰期）、50:50 FSH21/18:FSH24（围绝经期）或 20:80 FSH21/18:FSH24（绝经）处理，最长达 96 小时。与对照组相比，FSH21/18 和 80:20 FSH21/18:FSH24 增加了卵泡生长，而 FSH24 和 20:80 FSH21/18:FSH24 则相反。用 FSH24 或 20:80 FSH21/18:FSH24 处理的卵泡存活率降低，卵泡发生基底膜破裂和卵母细胞挤出，Caspase3 基因和蛋白表达增加，FSH24 或 20:80 FSH21/18:FSH24 处理的卵泡细胞增殖标志物减少。此外，这与调节卵泡功能的关键基因的差异调节有关。关键 FSH 信号通路的药理学抑制剂表明，FSH21/18 和 FSH24 启动不同的 FSHR 信号通路激活，这可能决定它们对卵泡生长和存活的不同影响。这些数据表明，FSH 糖基化的性质调节卵泡细胞环境，以调节卵泡生长和存活，并可能构成衰老过程中观察到的卵巢对 FSH 抵抗力增加的基础。
